AD is a progressive neurodegenerative disease with increasing incidence as the population lives longer and longer. Between 1980 and 2000, the number of Americans diagnosed with AD more than doubled with current estimates of about 24 million people worldwide. AD usually occurs in people over 65 years old and is the most common cause of dementia in adults, gradually destroying a person's memory and ability to learn, reason, make judgments, communicate and carry out daily activities. In later stages, patients may experience changes in personality and behavior, such as anxiety, suspicion, agitation and aggression. Delusions and hallucinations may also occur. The average life expectancy is approximately seven years.
Presently, the only way to diagnose AD with certainty is by autopsy. However, a clinical diagnosis of AD is typically determined through a series of evaluations in patients presenting with memory loss and other features of cognitive decline. The diagnostic workup includes a medical history, general physical and neurological examination, and administration of a cognitive test battery to assess mental function. The cognitive test battery often includes standardized cognitive screening tests such as the Mini-Mental State Examination (MMSE). A patient's cognitive test battery results are often considered in combination with existing clinical information and laboratory test results to assess the patient. Upon reaching a diagnosis of AD, a physician will further classify the disease as mild (early stage), moderate, or severe (late stage).
The defining lesions of AD are neurofibrillary tangles (NFTs) and senile plaques formed by neuronal accumulations of abnormal tau protein filaments and extracellular deposits of A-fibrils, respectively, both of which are implicated in mechanisms of AD brain degeneration. On the other hand, frontotemporal dementia (FTD) is associated with a broad spectrum of pathologies that may be characterized by abnormalities in tau, as well as ubiquitin positive inclusions. The early diagnosis of disorders such as FTD and AD, when therapy is likely to have the greatest impact, may be beneficial. The benefit may extend to monitoring patient responses to new therapeutic interventions in clinical trials. Biomarkers can also assist in overcoming some of the obstacles presented by the complexity of neurodegenerative diseases which are exemplified by neuro-degenerative tauopathies, a number of which overlap, since the biomarkers can provide objective surrogate markers of the disease and disease severity.
Improved means of diagnosing AD earlier and more accurately are required. Ultimately, there is a need for a reliable, valid, inexpensive, and early diagnostic test that can be used in any doctor's office.
There is evidence suggesting inflammation as a factor in the pathogenesis of AD. Research has been conducted to evaluate the potential of IL-1β, IL2, IL6, IL12, IL18 and TNF-α as biomarkers of AD and as a means to distinguish AD from other dementias (Guerreiro et al. (2007) Neurodegenerative Disease 4(6):406-412; Ozturk at al. (2007) Behavioural Neurology 18(4):207-215; Tan et al. (2007) Neurology 68(22):1902-1908). The data suggested higher levels of TNF-α and other pro-inflammatory cytokines could be predictive of risk of AD and could be used to assist in the diagnosis of AD.
In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness of the brain followed by a change in behaviour. When activation of the peripheral immune system continues, such as during systemic infections, autoimmune diseases, or chronic illness, the immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms. There is a body of evidence that inflammatory mediators may contribute to changes in brain. The first demonstration that peripherally administered bacterial toxin, lipopolysaccharide (LPS) induces the expression of interleukin (IL)-1β in the brain of rats (van Dam et al., 1992). This article was followed by many studies looking in mice, rats and human cells in vitro expose to LPS (Laye et al. 1994; Lombardi et al., 1999; Dziedzica et al., 2003) or stimulated with beta-amyloid that produce different cytokines (DelBo et al., 1995; Blasko et al., 1999; Meda et al. 1999). Tumor necrosis factor alpha, TNF-α- and IL-1β-induced sickness behaviour was observed (Huberman et al., 1994; Benveniste et al., 1999) in cells in vitro. Frohman et al., (1991) described expression of intercellular adhesion molecule 1 (ICAM-1) inAD. These data are consistent with the idea that in the brain, as in systemic organs, the natural balance between pro- and anti-inflammatory cytokines regulates the intensity and duration of the response to immune stimuli in patients with AD predisposing them to a pro-inflammatory phenotype (Akiyama et al., 2000; Remarque et al., 2001). There are studies that identify cytokines (transforming growth factor beta-TGF-beta (Chao et al., 1994; Flanders et al. 1995), intercellular adhesion molecule 1 (ICAM-1) (Frohman et al., 1991), Vascular endothelial factor (VEGF) elevated in serum of patients with vascular dementia. There is, however, a need for biomarkers that differentiate between AD and FTD.
A number of groups have identified novel biomarkers of AD and AD-like disorders and methods for assessment of AD and AD-like disorders. US Patent Application Publication No. 2007/0042429 describes a biomarker assay for differentiating between AD and AD-like disorders which utilizes 2-dimensional gel electrophoresis. Gel electrophoresis is also described in International Patent Application Publication No. WO/2004/001421 as a method for diagnosis and differential diagnosis of mental disorders.
US Patent Application Publication No. 2007/0037200 describes methods and compositions for diagnosing, stratification, and monitoring of AD and other neurological disorders as reflected in various body fluids.
Potential biomarkers of AD are disclosed in International Patent Application Publication Nos. WO05/052592, WO06/133423, WO06/028586, WO05/047484, WO06/113289, WO04/019043, and WO06/003414.
While AD is the most common type of dementia accounting for 60-80% of all cases of dementia, other causes of dementia may manifest similarly. One such AD-like disorder is frontotemporal dementia (FTD), which accounts for as many as 20% of dementias presenting under age 65. Because of its symptoms, FTD is commonly diagnosed as AD. FTD affects the frontal and temporal lobes of the brain and is associated with more rapid onset compared to AD. The frontotemporal lobar neuronal degeneration observed in FTD patients is believed to be associated with apoptosis events precipitated by activated macrophages and astrocytes.
FTD and AD are neurological disorders characterized by anterior and posterior brain damage, respectively. The differences in neuroanatomical structures affected by the disorders may also reflect different biomarker profiles. In FTD, products of activated macrophages and astrocytes lead to central nervous system dysfunction by directly damaging neurons by induction of altered gene and protein expression profiles. Inflammation corresponding to AD is primarily due to elevated levels of pro-inflammatory cytokines, the main cytokine being tumor necrosis factor alpha (TNF-α).
Despite the numerous differences between FTD and AD, there is overlap in clinical presentation. For example, Binetti et al. (Arch Neurol (2000) 57:225-232) reported findings in 121 patients with AD and 44 patients with Pick's disease (i.e., FTD). The authors showed that cognitive test performance did not clearly distinguish between the two groups. In addition, patients with AD can have behavioural changes suggestive of frontal lesions, such as apathy and euphoria, although these abnormalities are more prominent in FTD. Despite similarities between FTD and AD, such as those found by Binetti et al., the two are separate disease entities.
AD differs from FTD in neuropathology, neurochemistry, genetics, distribution of lesions, and clinical presentation. The histopathology is distinct from FTD and includes neuritic plaques, neurofibrillary tangles, loss of synapses and neurons, granulovacuolar degeneration, AMY plaques, and amyloid angiopathy. In addition, there is a prominent cholinergic deficit in AD with a marked and consistent deficiency in choline acetyltransferase and acetylcholine synthesis (Arriagada P V, Growdon J H, Hedley-Whyte E T, Hyman B T. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology 1992; 42(3):631-639), whereas there is no cholinergic deficit in FTD (Hof et al. Arch Neurol (1992) 49:946-953). At least 4 genes with loci on chromosomes 1, 14, 19, and 21, respectively, have been linked to AD (Mathuranath et al. Neurology (2000) 55:1613-1620), whereas mutations on chromosome 17 have been related to FTD (Bird et al. Neurobiol Aging (2001) 22:113-114). Also in contrast to FTD is the distribution of pathological changes in AD, which involve primarily posterior brain structures, as opposed to anterior brain damage in FTD (Neary D. Frontotemporal degeneration, Pick disease, and corticobasal degeneration. One entity or 3? Arch Neurol 1997; 54:1425-1426).
In addition to the above, there are striking clinical differences between AD and FTD (Nearye et al. Arch Neurol (1997) 54:1425-1426). These include preserved ability to interact well at an interpersonal level and preservation of social graces, manners and courtesy until late in AD versus early and prominent decline in social interpersonal conduct in FTD. There is also early and pervasive memory loss, spatial disorientation, and aphasia in AD whereas in FTD memory loss is variable and is never the dominating feature, visuo-spatial function is preserved, and language is characterised by adynamic speech. Hodges et al. (Neuropsychology (1999) 13(1):31-40) presented differences between FTD and AD. This difference was based largely upon a lack of impairment in FTD on neuropsychological measures compared to impaired performance in AD. Thus, FTD and AD are distinctly different disorders and are well-suited as models of anterior and posterior dementias.
There remains a need to identify biomarkers that distinguish between AD and AD-like disorders such as FTD, especially as there are therapies that are recommended for AD but do not work in FTD (Binetti G, Locascio J J, Corkin S, Vonsattel J P, Growdon J H. Differences between Pick disease and Alzheimer disease in clinical appearance and rate of cognitive decline. Arch Neurol 2000; 57:225-232). Identification of such biomarkers will provide a means to assist diagnosis, enabling earlier and more relevant treatment interventions.